Future Therapy

A more detailed understanding of molecular mechanisms involved in meningioma tumori-genesis has opened the door for new anticancer treatment approaches that are based on the concept of target-specific therapies. Molecular-based treatment strategies targeting the precise molecular abnormalities that create and drive the neoplastic phenotype offer a great hope as future meningioma treatments. These approaches include gene therapy to restore the functions of inactivated NF-2 gene and other meningioma-associated tumor suppressors, and the use of gene therapy or several promising small molecule agents that inhibit signal transduction molecules responsible for overac-tivation of the growth factor/Ras signaling pathway.

Besides trying to replace a defective tumor suppressor gene with a functional allele, or to deliver genes that can help kill tumor cells, gene therapy technology encompasses many additional applications, such as adoptive immunotherapy, anti-angiogenesis, and anti-telomerase approaches to cancer treatment. For example, virus-mediated delivery was successfully used to introduce functional NF-2 tumor suppressor gene into NF-2-gene-deficient meningioma cell lines. It is likely that such an approach can be used to deliver other menin-gioma-associated tumor suppressor genes, such as DAL-1 and p53, to target early and late stages of meningioma progression, respectively.

The elevated expression of a large number of polypeptide growth factors and their tyrosine kinase receptors is a hallmark of menin-gioma tumorigenesis. Many polypeptide growth factors implicated in meningioma tumorigene-sis transduce their proliferative signal through Ras proteins. As expected, inhibition of Ras proteins by the adenovirus-mediated transfer of the dominant negative Ras mutant potently suppressed proliferation of exponentially growing and growth-arrested meningioma cells stimu lated with serum. As shown in several models, another anti-cancer gene therapy approach to specifically target Ras proteins is to use antisense oligonucleotide inhibitors or antisense ribozymes, catalytic RNA molecules [46,47]. Another attractive molecular target of the growth factor activated Ras pathway is the Raf-1 protein. The application of the antisense oligonucleotide directed against the human Raf-

I kinase (ISIS 3521) has now reached the phase

II stage of anti-cancer therapy development. If the evidence for anti-tumor effect is provided, this therapeutic approach may be applied to meningioma treatment in the future.

Anti-angiogenic gene therapy approaches are particularly attractive for meningioma treatment because of the well-documented role of VEGF in meningioma tumorigenesis and tumor recurrence. Targeting of telomerase represents an exciting new approach to cancer therapy. Because telomerase activation occurs frequently in atypical and anaplastic meningiomas, and anti-telomerase gene therapy approaches have been successfully used in animal and tissue culture models for treatment of malignant gliomas and other malignancies, there is no reason to question the applicability of this gene therapy approach to the treatment of menin-giomas. The major limiting factor of successful clinical use of gene therapy for treatment of cancer, including meningiomas, is the lack of selectivity and low efficiency of the currently available vector delivery systems. Improved vectors and anti-sense oligonucleotides, and new formulations for enhanced delivery, are likely to circumvent degradation and delivery difficulties and thus improve the clinical application of gene therapy technology.

At present, however, treatment of menin-giomas by small molecule compounds that target molecular abnormalities can be a more promising approach to treat meningiomas in humans. For example, recently developed selective kinase inhibitors of PDGF, EGF and VEGF receptors may one day serve as novel therapeutic agents for the treatment of meningiomas [48]. Unfortunately, it is not clear which PTK receptors are the most critical in meningioma tumorigenesis, and therefore, simultaneous specific targeting of several PTK receptors, or use of broad-spectrum PTK inhibitors, is likely to be required to achieve therapeutic response in humans.

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